Rotenone Attenuates Renal Injury in Aldosterone-Infused Rats by Inhibiting Oxidative Stress, Mitochondrial Dysfunction, and Inflammasome Activation

Ding, Wei; Cheng, Xu; Wang, Bin

doi:10.12659/msm.895945

Cited by 36 publications

(22 citation statements)

References 28 publications

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“…Thus, a suitable inhibition of the activity of the injured mitochondria could restrict the release of ROS and other toxic products to attenuate the organ injury. In agreement with this concept, a number of literatures documented that the inhibition of mitochondrial complex I activity under pathological conditions protected against the organ damage [22,[34][35][36][37][38]. In the present study, we also found that mitochondrial complex I inhibitor rotenone protected against APAP-induced acute kidney injury.…”

Section: Discussionsupporting

confidence: 91%

Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation

et al. 2018

Kidney Blood Press Res

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Background/Aims: In clinic, excessive acetaminophen (APAP) can cause kidney damage with uncertain mechanisms. Recently, accumulating evidence demonstrated a pathogenic role of mitochondrial dysfunction in the kidney injury. Thus, in this study, rotenone, a mitochondrial complex I inhibitor, was applied to the mice with APAP-induced acute kidney injury to evaluate the effect of mitochondrial complex I inhibition on APAP nephrotoxicity. Methods: After 3 days of rotenone pretreatment, mice were administered with APAP (300mg/kg) by intraperitoneal injection for 24 h. Then the kidney injury, inflammation, and oxidative stress were evaluated. Results: APAP significantly enhanced the BUN, serum creatine, and cystatin C levels in line with a moderate alteration of renal morphology. Strikingly, rotenone treatment normalized BUN, serum creatinine, and cystatin C levels, as well as the kidney morphology. Meanwhile, APAP enhanced tubular injury markers of NGAL and KIM-1 by 347- and 5-fold at mRNA levels, respectively. By Western blotting, we confirmed a 15-fold increment of NGAL in APAP-exposed kidneys. Importantly, rotenone treatment largely normalized NGAL and KIM-1 levels and attenuated inflammatory response in APAP-treated mice. Similarly, rotenone treatment enhanced the expressions of SOD1-3 compared with APAP group in line with a significant suppression of kidney MDA content. Finally, we observed that inhibition of mitochondrial complex III failed to protect against APAP-induced nephrotoxicity. Conclusion: Mitochondrial complex I inhibitor rotenone protected kidneys against APAP-induced injury possibly via the inhibition of mitochondrial oxidative stress and inflammation.

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Section: Discussionsupporting

confidence: 91%

Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation

et al. 2018

Kidney Blood Press Res

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“…We previously demonstrated that mitochondrial ROS (mtROS) contribute to Aldo-induced renal tubular injury in vitro . We also showed that rotenone, an inhibitor of mitochondrial complex I, attenuated Aldo-induced renal injury by inhibiting oxidative stress and mitochondrial dysfunction [9, 10]. These results suggest MtD is an important factor in Aldo-induced kidney disease.…”

Section: Introductionmentioning

confidence: 89%

“…We cut ultrathin sections on a microtome, placed them on copper grids, stained them with uranyl acetate and lead citrate, and visualized them with an electron microscope. All these experiments were performed as described previously [10]. …”

Section: Methodsmentioning

confidence: 99%

Mitochondria-Targeted Antioxidant Mito-Tempo Protects Against Aldosterone-Induced Renal Injury In Vivo

Ding

Liu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Growing evidence suggests mitochondrial dysfunction (MtD) and the Nlrp3 inflammasome play critical roles in chronic kidney disease (CKD) progression. We previously reported that Aldosterone (Aldo)-induced renal injury in vitro is directly caused by mitochondrial reactive oxygen species (mtROS)-mediated activation of the Nlrp3 inflammasome. Here we aimed to determine whether a mitochondria-targeted antioxidant (Mito-Tempo) could prevent Aldo-induced kidney damage in vivo. Methods: C57BL/6J mice were treated with Aldo and/or Mito-Tempo (or ethanol as a control) for 4 weeks. Renal injury was evaluated by Periodic Acid-Schiff reagent or Masson’s trichrome staining and electron microscopy. ROS were measured by DCFDA fluorescence and ELISA. MtD was determined by real-time PCR and electron microscopy. Activation of the Nlrp3 inflammasome and endoplasmic reticulum stress (ERS) was detected via western blot. Results: Compared with control mice, Aldo-infused mice showed impaired renal function, increased mtROS production and MtD, Nlrp3 inflammasome activation, and elevated ERS. We showed administration of Mito-Tempo significantly improved renal function and MtD, and reduced Nlrp3 inflammasome activation and ERS in vivo. Conclusion: Mitochondria-targeted antioxidants may attenuate Aldo-infused renal injury by inhibiting MtD, the Nlrp3 inflammasome, and ERS in vivo. Therefore, targeting mtROS might be an effective strategy for preventing CKD.

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“…Real-time PCR was performed using the ABI 7500 real-time PCR system (Applied Biosystems). The following SYBR green real-time PCR primers were used: CTGF, forward 5′-GAGGAAAACATTAAGAAGGGCAAA-3′; reverse 5′-CGGCACAGGTCTTGATGA-3′; TGF-β, forward 5′-GAGGTGACCTGGGCACCAT-3′; reverse 5′-GGCCATGAGGAGCAGGAATCCTGCTGG-3′; collagen IV, forward 5′-ATCATTGCCATCTGGAGACACCT-3′; reverse 5′-TACCATTTCTTCAACCTGGGAGC-3′; IL-1β, forward 5′-AGCCTTTGTCCTCTGCCAAGT-3′; reverse 5′-CCAGAATGTGCCACGGTTTT-3′; ATP synthase, forward 5ʹ-TCCATCAAAAACATCCAGAAAA-3ʹ; reverse 5ʹ-GAGGAGTGAATAGCACCACAAA-3ʹ; 18S, forward 5ʹ-TTCGGAACTGAGGCCATGATT-3ʹ; reverse 5ʹ-TTTCGCTCTGGTCCGTCTTG-3ʹ; and mtDNA, forward 5ʹ-TTTTATCTGCATCTGAGTTTAATCCTGT-3ʹ; reverse 5ʹ-CCACTTCATCTTACCATTTATTATCGC-3ʹ [7,23].…”

Section: Real-time Pcrmentioning

confidence: 99%

“…We had previously determined that the mitochondrial complex I inhibitor rotenone attenuated aldosterone-infused rats by inhibiting oxidative stress and MtD. The mitochondria could be the first injury target of mitochondrial-derived ROS, forming a positive pathogenic crosstalk between mitochondrial-derived ROS and MtD [7,8]. Ang II has been shown to play an important role in mitochondrial homeostasis.…”

Section: Introductionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 Attenuates Angiotensin II-Induced Renal Injury by Inhibiting Mitochondrial Dysfunction and Autophagy

Shen

Ling

et al. 2018

Cell Physiol Biochem

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Background/Aims: A recent study has shown that 1,25-dihydroxyvitamin D3 (1,25-D3), the active form of vitamin D, can ameliorate renal dysfunction. In this study, we aimed to determine the role of 1,25-D3 in angiotensin (Ang II)-induced renal injury and investigate the underlying mechanisms involved. Methods: C57BL/6J mice were treated with Ang II and/or 1,25-D3 (or saline as the control) for 2 weeks. Renal injury was evaluated using transmission electron microscopy and periodic acid-Schiff reagent and Masson’s trichrome staining. The pro-fibrotic and pro-inflammatory factors were assessed using real-time PCR. The renal apoptotic pathway was evaluated with TUNEL staining and western blot. Mitochondrial dysfunction (MtD) was determined using real-time PCR and electron microscopy. The activation of autophagy was detected using western blot. Results: In the Ang II-infused mice, expanded mesangial regions, tubulointerstitial fibrosis, and foot process fusion were observed; the levels of the pro-fibrotic and pro-inflammatory cytokines and MtD were also increased when compared with the control group. However, we found that administration of 1,25-D3 significantly improved renal function and MtD and reduced the pro-fibrotic and pro-inflammatory cytokine levels. Furthermore, 1,25-D3 significantly inhibited Ang II-induced autophagy dysfunction (determined by inhibition of Beclin-1 activation and reduction of the LC3-II/LC3-I ratio). Conclusion: Our findings suggest that 1,25-D3 may attenuate Ang II-induced renal injury by improving MtD and modulating autophagy. 1,25-D3 may be a new therapeutic for the treatment of CKD.

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Rotenone Attenuates Renal Injury in Aldosterone-Infused Rats by Inhibiting Oxidative Stress, Mitochondrial Dysfunction, and Inflammasome Activation

Cited by 36 publications

References 28 publications

Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation

Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation

Mitochondria-Targeted Antioxidant Mito-Tempo Protects Against Aldosterone-Induced Renal Injury In Vivo

1,25-Dihydroxyvitamin D3 Attenuates Angiotensin II-Induced Renal Injury by Inhibiting Mitochondrial Dysfunction and Autophagy

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